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Elucidation of genetic factors and mechanisms involved in the development and progression of type 2 diabetes using a novel rat model of the disease

Research Project

Project/Area Number 18H02364
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Review Section Basic Section 42040:Laboratory animal science-related
Research InstitutionKyoto University (2019-2020)
Kobe University (2018)

Principal Investigator

YOKOI Norihide  京都大学, 農学研究科, 教授 (70311610)

Co-Investigator(Kenkyū-buntansha) 谷口 幸雄  京都大学, 農学研究科, 准教授 (10252496)
波多野 直哉  神戸大学, 医学研究科, 医学研究員 (10332280)
須山 幹太  九州大学, 生体防御医学研究所, 教授 (70452365)
Project Period (FY) 2018-04-01 – 2021-03-31
Project Status Completed (Fiscal Year 2020)
Budget Amount *help
¥17,550,000 (Direct Cost: ¥13,500,000、Indirect Cost: ¥4,050,000)
Fiscal Year 2020: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000)
Fiscal Year 2019: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000)
Fiscal Year 2018: ¥7,410,000 (Direct Cost: ¥5,700,000、Indirect Cost: ¥1,710,000)
Keywords糖尿病 / 疾患モデル / 遺伝素因 / 病態発症機構 / オミクス / 膵島障害
Outline of Final Research Achievements

In this study, by using the Zucker fatty diabetes mellitus (ZFDM) rat, a novel rat model of type 2 diabetes which has been developed by the representative researcher’s group, we performed genetic analysis and exome analysis to identify diabetes susceptibility genes, CRISPR/Cas9-mediated genome editing of the candidate gene to verify the causality, mRNA-sequencing and metabolome analysis to elucidate longitudinal changes in metabolic dysfunction, and proteome analysis to identify abnormally modified proteins, resulting in the clarification of a part of genetic factors and mechanisms involved in the development and progression of the disease.

Academic Significance and Societal Importance of the Research Achievements

本研究により明らかとなったZFDMラットにおける遺伝素因と膵島障害の発症・進展機構は、ヒト糖尿病の遺伝素因と病態発症・進展機構の解明や新規のメカニズムに基づく治療薬の開発の基盤となると考えられる。また、同様の研究手法が適用可能な様々の研究分野において疾患モデルの有用性を実証するものである。

Report

(4 results)
  • 2020 Annual Research Report   Final Research Report ( PDF )
  • 2019 Annual Research Report
  • 2018 Annual Research Report
  • Research Products

    (28 results)

All 2021 2020 2019 2018 Other

All Int'l Joint Research (1 results) Journal Article (10 results) (of which Int'l Joint Research: 5 results,  Peer Reviewed: 9 results,  Open Access: 9 results) Presentation (15 results) (of which Invited: 3 results) Remarks (2 results)

  • [Int'l Joint Research] University of Washington, Seattle/University of Illinois at Chicago/University of Chicago(米国)

    • Related Report
      2019 Annual Research Report
  • [Journal Article] Glutamate is an essential mediator in glutamine‐amplified insulin secretion2021

    • Author(s)
      Han Guirong、Takahashi Harumi、Murao Naoya、Gheni Ghupurjan、Yokoi Norihide、Hamamoto Yoshiyuki、Asahara Shun‐ichiro、Seino Yutaka、Kido Yoshiaki、Seino Susumu
    • Journal Title

      Journal of Diabetes Investigation

      Volume: - Issue: 6 Pages: 920-930

    • DOI

      10.1111/jdi.13497

    • NAID

      120007097043

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] GCN2 regulates pancreatic β-cell mass by sensing intracellular amino acid levels.2020

    • Author(s)
      Kanno A, Asahara SI, Furubayashi A, Masuda K, Yoshitomi R, Suzuki E, Takai T, Kimura-Koyanagi M, Matsuda T, Bartolome A, Hirota Y, Yokoi N, Inaba Y, Inoue H, Matsumoto M, Inoue K, Abe T, Wei FY, Tomizawa K, Ogawa W, Seino S, Kasuga M, Kido Y.
    • Journal Title

      JCI Insight.

      Volume: 5 Issue: 9 Pages: 128820-128820

    • DOI

      10.1172/jci.insight.128820

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Tumor-like features of gene expression and metabolic profiles in enlarged pancreatic islets are associated with impaired incretin-induced insulin secretion in obese diabetes: a study of ZFDM rat.2020

    • Author(s)
      Hayami T, Yokoi N, Yamaguchi T, Honda K, Murao N, Takahashi H, Wang S, Seino Y, Kamiya H, Yabe D, Sweet IR, Mizoguchi A, Nakamura J, Seino S
    • Journal Title

      J Diabetes Investig

      Volume: - Issue: 6 Pages: 1434-1447

    • DOI

      10.1111/jdi.13272

    • Related Report
      2020 Annual Research Report 2019 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Gs/Gq signaling switch in β cells defines incretin effectiveness in diabetes2020

    • Author(s)
      Oduori Okechi S.、Murao Naoya、Shimomura Kenju、Takahashi Harumi、Zhang Quan、Dou Haiqiang、Sakai Shihomi、Minami Kohtaro、Chanclon Belen、Guida Claudia、Kothegala Lakshmi、Tol? Johan、Maejima Yuko、Yokoi Norihide、Minami Yasuhiro、Miki Takashi、Rorsman Patrik、Seino Susumu
    • Journal Title

      Journal of Clinical Investigation

      Volume: 130 Issue: 12 Pages: 6639-6655

    • DOI

      10.1172/jci140046

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] 動物モデルを用いた1型糖尿病の遺伝因子の同定と病態解明2020

    • Author(s)
      横井伯英
    • Journal Title

      糖尿病・内分泌代謝科

      Volume: 51 Pages: 266-273

    • Related Report
      2020 Annual Research Report
  • [Journal Article] Glutamate as intracellular and extracellular signals in pancreatic islet functions2019

    • Author(s)
      Takahashi H, Yokoi N, Seino S
    • Journal Title

      Proceedings of the Japan Academy, Series B

      Volume: 95 Issue: 6 Pages: 246-260

    • DOI

      10.2183/pjab.95.017

    • NAID

      130007662352

    • ISSN
      0386-2208, 1349-2896
    • Year and Date
      2019-06-11
    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Arsenic modifies serotonin metabolism through glucuronidation in pancreatic β-cells2019

    • Author(s)
      Carmean Christopher M.、Yokoi Norihide、Takahashi Harumi、Oduori Okechi S.、Kang Christie、Kanagawa Akiko、Kirkley Andrew G.、Han Guirong、Landeche Michael、Hidaka Shihomi、Katoh Miki、Sargis Robert M.、Seino Susumu
    • Journal Title

      American Journal of Physiology-Endocrinology and Metabolism

      Volume: 316 Issue: 3 Pages: E464-E474

    • DOI

      10.1152/ajpendo.00302.2018

    • Related Report
      2019 Annual Research Report 2018 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Functional adenosine triphosphate-sensitive potassium channel is required in high-carbohydrate diet-induced increase in β-cell mass.2019

    • Author(s)
      Murase M, Seino Y, Maekawa R, Iida A, Hosokawa K, Hayami T, Tsunekawa S, Hamada Y, Yokoi N, Seino S, Hayashi Y, Arima H
    • Journal Title

      J Diabetes Investig

      Volume: 10(2) Issue: 2 Pages: 238-250

    • DOI

      10.1111/jdi.12907

    • NAID

      120006599162

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Characteristics of repaglinide effects on insulin secretion.2018

    • Author(s)
      Takahashi H, Hidaka S, Seki C, Yokoi N, Seino S.
    • Journal Title

      Eur J Pharmacol.

      Volume: 828 Pages: 52-59

    • DOI

      10.1016/j.ejphar.2018.03.025

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Inhibition of SNAT5 Induces Incretin-Responsive State From Incretin-Unresponsive State in Pancreatic β-Cells: Study of β-Cell Spheroid Clusters as a Model2018

    • Author(s)
      Hashim Mahira、Yokoi Norihide、Takahashi Harumi、Gheni Ghupurjan、Okechi Oduori S.、Hayami Tomohide、Murao Naoya、Hidaka Shihomi、Minami Kohtaro、Mizoguchi Akira、Seino Susumu
    • Journal Title

      Diabetes

      Volume: 67 Issue: 9 Pages: 1795-1806

    • DOI

      10.2337/db17-1486

    • NAID

      40022150466

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Presentation] 耐糖能ならびに膵β細胞機能の加齢性変化の解明2020

    • Author(s)
      村尾直哉、横井伯英、速水智英、髙橋晴美、清野 進
    • Organizer
      第63回日本糖尿病学会年次学術集会
    • Related Report
      2020 Annual Research Report
  • [Presentation] 肥満糖尿病の膵島における、タンパク質のO-結合型糖鎖修飾に関連したインクレチン応答性障害の機序の解明2020

    • Author(s)
      吉田 舞, 横井 伯英, 速水 智英, 高橋 晴美, 小川 渉, 清野 進
    • Organizer
      第63回日本糖尿病学会年次学術集会
    • Related Report
      2020 Annual Research Report
  • [Presentation] グルタミンによるインスリン分泌増強機構の解明2020

    • Author(s)
      韓 桂栄, 髙橋晴美, 村尾直哉, ゲニ グブルジャン, 太田新菜, 浜本芳之, 清野 裕, 横井伯英, 木戸良明, 清野 進
    • Organizer
      第63回日本糖尿病学会年次学術集会
    • Related Report
      2020 Annual Research Report
  • [Presentation] Gs to Gq signaling switch in b-cells due to persistent depolarization determines effective insulin secretion-based drugs2020

    • Author(s)
      Okechi OS, Murao N, Shimomura K, Zhang Q, Dou H, Takahashi H, Maejima Y, Minami K, Yokoi N, Miki T, Rorsman P, Seino S
    • Organizer
      第63回日本糖尿病学会年次学術集会
    • Related Report
      2020 Annual Research Report
  • [Presentation] 肥満糖尿病の膵島におけるインクレチン応答性障害の発症機序2020

    • Author(s)
      速水智英、横井伯英、吉田 舞、本田洸平、高橋晴美、神谷英紀、溝口 明、中村二郎、清野 進
    • Organizer
      第34回日本糖尿病・肥満動物学会年次学術集会
    • Related Report
      2019 Annual Research Report
  • [Presentation] 医学とアミノ酸2019

    • Author(s)
      横井伯英
    • Organizer
      第73回日本栄養・食糧学会大会
    • Related Report
      2019 Annual Research Report
    • Invited
  • [Presentation] 肥満糖尿病における膵島機能不全の機序の解明2019

    • Author(s)
      吉田 舞, 横井 伯英, 速水 智英, 川畑 綾子, 高橋 晴美, 小川 渉, 清野 進
    • Organizer
      第62回日本糖尿病学会年次学術集会
    • Related Report
      2019 Annual Research Report
  • [Presentation] Role of glutamate signaling in insulin secretion2019

    • Author(s)
      Norihide Yokoi, Harumi Takahashi, Susumu Seino
    • Organizer
      第62回日本糖尿病学会年次学術集会
    • Related Report
      2019 Annual Research Report
    • Invited
  • [Presentation] 糖尿病の遺伝素因の解明-動物モデルを用いたアプローチ-2019

    • Author(s)
      横井伯英
    • Organizer
      関西実験動物研究会第144回研究会
    • Related Report
      2019 Annual Research Report
    • Invited
  • [Presentation] Elucidation of genetic factors and pathogenesis of obese diabetes: Study of ZFDM rat2019

    • Author(s)
      Norihide Yokoi, Tomohide Hayami, Mai Yoshida, Harumi Takahashi, Yukio Taniguchi, Susumu Seino
    • Organizer
      第42回日本分子生物学会年会
    • Related Report
      2019 Annual Research Report
  • [Presentation] 肥満2型糖尿病における肥大膵島は未分化細胞や癌細胞に類似した代謝様式に変化し、インクレチン応答性障害を呈する2019

    • Author(s)
      速水智英, 横井伯英, 本田洸平, 高橋晴美, 神谷英紀, 溝口明, 中村二郎, 清野 進
    • Organizer
      第33回日本糖尿病・肥満動物学会
    • Related Report
      2018 Annual Research Report
  • [Presentation] 肥満糖尿病モデルZFDMラットの膵島におけるタンパク質糖鎖修飾の病態生理学的意義2018

    • Author(s)
      横井伯英、速水智英、波多野直哉、日高志保美、川畑綾子、星野貴一、星野雅行、清野 進
    • Organizer
      第65回日本実験動物会総会
    • Related Report
      2018 Annual Research Report
  • [Presentation] 肥満糖尿病の膵島におけるインクレチン応答性障害―オミクス解析による検討―2018

    • Author(s)
      速水智英, 横井伯英, 日高志保美, 川畑綾子, グプルジャン ゲニ, マヒラ アシム, 高橋晴美, 神谷英紀, 清野 裕, 中村二郎, 清野 進
    • Organizer
      第61回日本糖尿病学会年次学術集会
    • Related Report
      2018 Annual Research Report
  • [Presentation] 肥満2型糖尿病では肥大した膵島における糖代謝異常とO-GlcNAc化の亢進がインクレチン応答性インスリン分泌障害を引き起こす2018

    • Author(s)
      横井伯英、速水智英、吉田 舞、高橋晴美、清野 進
    • Organizer
      第41回日本分子生物学会年会
    • Related Report
      2018 Annual Research Report
  • [Presentation] 肥満糖尿病モデルZFDMラットにおけるインクレチン作用障害の発症機序2018

    • Author(s)
      横井 伯英、速水 智英、川畑 綾子、星野 貴一、星野 雅行、清野 進
    • Organizer
      第140回関西実験動物研究会
    • Related Report
      2018 Annual Research Report
  • [Remarks] 京都大学大学院農学研究科動物遺伝育種学分野ホームページ

    • URL

      http://www.jkaabs.kais.kyoto-u.ac.jp/

    • Related Report
      2020 Annual Research Report 2019 Annual Research Report
  • [Remarks] 神戸大学大学院医学研究科 分子代謝医学部門ホームページ

    • URL

      http://www.med.kobe-u.ac.jp/phys1/

    • Related Report
      2018 Annual Research Report

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Published: 2018-04-23   Modified: 2022-01-27  

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